CN103179963B - Compositions for the abscisic acid of animal health - Google Patents
Compositions for the abscisic acid of animal health Download PDFInfo
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- CN103179963B CN103179963B CN201180044937.3A CN201180044937A CN103179963B CN 103179963 B CN103179963 B CN 103179963B CN 201180044937 A CN201180044937 A CN 201180044937A CN 103179963 B CN103179963 B CN 103179963B
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Classifications
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A23K20/10—Organic substances
- A23K20/105—Aliphatic or alicyclic compounds
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/50—Feeding-stuffs specially adapted for particular animals for rodents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
- A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
The present invention relates to the compositions comprising abscisic acid and/or its salt, derivant and analog and use the health of described composition for improved animal and the method for young baby's mortality rate.
Description
Technical field
The present invention relates generally to the compositions comprising abscisic acid and/or its salt, derivant and analog, and they preparation methoies and the application process in animal and nutraceutical use.
Background technology
Phytohormone that abscisic acid is naturally-occurring and be the material of a kind of safety non-toxic.The chemical property of abscisic acid and the like and physiological function are by Milborrow, Ann.Rev.PlantPhysiol.1974,25, and 259-307 describes.The naturally occurring enantiomeric form of abscisic acid be (S)-(+)-abscisic acid.The spatial chemistry of the main part side chain of naturally occurring abscisic acid be 2-cis-, 4-is trans-, it is the isomer synthetically produced by all green plantss and some microorganism biologicals.
But, such as U. S. application 12/011,846,12/011,825,61/083,202,61/083,203 and PCT/US08/01203 described in, some salt of abscisic acid and/or its derivant and analog, has shown that the high concentration of abscisic acid in their compositions and is expressly incorporated herein.
The commercial formulation comprising abscisic acid agricultural and gardening in be used on crops and plant or around to improve stress tolerance, to slow down the speed of growth and florescence alternation.Abscisic acid has been in the news and has had insect inhibitory matter.Referring to U.S. Patent No. 4,434,180 and No. 4,209,530.Other people are it have been reported that the possible medicinal characteristic of abscisic acid, for instance United States Patent (USP) provisional application the 2006/0292215th openly use abscisic acid for the method for anticancer purpose No. WO2007/042983 anti-inflammatory activities disclosing abscisic acid of international application.The content of these patents is incorporated by reference into.
Herein, applicant has now surprisingly found that abscisic acid and/or its salt, derivant and analog have nutriment characteristic in animal.
Summary of the invention
The present invention relates generally to the compositions comprising abscisic acid and/or its salt, derivant and analog (overall also referred to as " ABA " herein) and their methods of being used as nutriment, (S)-(+)-abscisic acid is a kind of enantiomer (hereafter " S-ABA ") of abscisic acid.It is found by the applicant that the compositions of ABA can be used for treating various disease and may also used as nutriment.
The compositions of the present invention generally comprises ABA.Optionally comprise enhancing ABA other components bioactive.
Another embodiment of the invention relates to the treatment to diabetes, and including reducing the method for blood glucose levels and reducing the method for triglycerides in blood, described method includes the ABA of effective amount on animal administering therapeutic.
In also having an embodiment, the method for survival rate and body weight after the present invention relates to breeding and relating more specifically to increase birth, described method includes the ABA of effective amount on the suckling parent administering therapeutic of animal in need or animal in need.
Another embodiment of the invention relates to the method increasing immunologic function, and described method includes the ABA of effective amount on animal administering therapeutic in need.This immunologic function is likely to indicate via minimizing observable in the size of spleen at least partially, because many patient's condition-and from infection to hepatopathy and some cancer-may result in the spleen expanded.
Finally, in another embodiment, the present invention relates to enhancing vigilance and treatment attention deficit disorder, it includes the ABA of effective amount on animal administering therapeutic.
Unless outside claim explicitly indicates that otherwise, disclosed embodiment is the simple examples embodiment of invention disclosed herein concept and should not be considered limiting.
Detailed description of the invention
The present invention relates generally to the compositions comprising ABA and their method being used as nutriment, wherein S-ABA is ABA enantiomer.It is found by the applicant that the compositions of ABA can be used for treating multiple disease and be used as nutriment, for infant formula or be used as composition of food.
Preferred ABA sum analogous to general Dedekind sum is defined by structure 1,2 and 3, wherein for structure 1:
The key in side chain 2 site is cis or trans double bond,
The key in side chain 4 site is cis or trans double bond, is cis or trans double or triple bonds,
The spatial chemistry of alcoholic hydroxyl group is S-, R-or R, S-mixture,
The spatial chemistry of R1 group is and the cis relation of alcoholic hydroxyl group,
R1=acetenyl, vinyl, cyclopropyl or trifluoromethy, and
R2=hydrogen or low alkyl group
Wherein, low alkyl group is defined as the straight or branched alkyl group comprising 1 to 4 carbon atom, and when having 3 or more carbon atom, it can comprise zero or ring or double bond.
For structure 2:
The key in side chain 2 site is cis or trans double bond,
The key in side chain 4 site is three keys,
The spatial chemistry of alcoholic hydroxyl is S-, R-or R, S-mixture.
R1=hydrogen or low alkyl group
Wherein, low alkyl group is defined as the straight or branched alkyl group comprising 1 to 4 carbon atom, and when having 3 or more carbon atom, it can comprise zero or ring or double bond.
For structure 3:
The key in side chain 2 site is cis or trans double bond,
The key in side chain 4 site is trans double bond,
The spatial chemistry of alcoholic hydroxyl is S-, R-or R, S-mixture.
R1=hydrogen or low alkyl group
Wherein, low alkyl group is defined as the straight or branched alkyl group comprising 1 to 4 carbon atom, and when having 3 or more carbon atom, it can comprise zero or ring or double bond.
The salt of analog includes sodium salt and lithium salts can be used for the present invention above.
S-ABA is the preferred compound of compositions herein and purposes and has having structure:
The compositions and methods of the invention contain all isomeric form of desired abscisic acid, their racemic mixture, enol form form, dissolving and undissolved form, analog, prodrug, derivant (including but not limited to ester and ether) and acceptable salt.The example of spendable applicable salt includes inorganic salt such as ammonium, lithium, sodium, potassium, magnesium and potassium salt and organic salt such as triethanolamine, diethanolamine and ethanolamine salt.In one embodiment, organic amine salt is triethanolamine salt.In another embodiment, organic amine salt is dimethyl ethanol amine salt.In yet another embodiment, organic amine salt is ethanolamine salt.These examples of salt are not intended to be likely to other salt of the purposes being equally applicable in the present invention.A kind of currently preferred salt is ammonium salt.Other preferred salt are sodium salt and potassium salt.Salt can be prepared by acid form contacts generation salt in a usual manner with the desired alkali of q.s.Free acid form can process salt by the aqueous sulfuric acid such as diluted by the aqueous acid solution of applicable dilution, hydrochloric acid or phosphoric acid and regenerate.Free acid form is slightly different in some physical property with the salt form of each of which, for instance they dissolubility in polar solvent, but for the purpose of the present invention, salt is equivalent to the free acid form of each of which.(referring to such as S.M.Berge, et al., " PharmaceuticalSalts, " J.Pharm.Sci., 66:1-19 (1977), it is expressly incorporated herein by application).
Definition
Term " prevention (preventing) " and " prevention (preventing) " refer to the preventative purposes of the probability of one or more symptoms of disease, disease or the patient's condition that this term of minimizing is applied to or these diseases, disease or the patient's condition.Without necessarily achieving the prevention probability of 100%；At least part of effect reaching to reduce the risk obtaining these diseases, disease or the patient's condition is sufficient to.
Term " animal " refers to the young baby of any animal or animal, and it is accepting treatment, needs treatment, is taking or accept the treatment of prevention purpose and/or be applied described compositions.Term " young baby " refers to filial generation or the daughter of animal, and includes the filial generation, fetus and the embryo that have been born." animal " should include but not limited to poultry, including chicken (including broiler and laying hen and male and female breeding original seed), geese and ducks, turkey, Phasiana, cornish hen, pig, cattle (including beef and dairy product), sheep and goat.Additionally, " animal " should include Silurus asotus fish, Cyprinus carpio, tilapia, Squaliobarbus ourriculus, huge legendary turtle shrimp, astacus, Lobster, Eriocheir sinensis, aquatic mammals, salmon and morrhua equally.
Term " compositions " includes comprising the product of ABA (and if show, with specific amount), including the product of the ABA with external source or rise, and directly or indirectly combines, from the specific components of ABA with specified quantitative, any product obtained.
Term administering (administering) " or " using (administration) " include introducing internal by the ABA of the present invention and other treatment agent, it is preferable that introduce any mode of body circulation.Example includes but not limited to be administered orally, direct oral cavity, through Sublingual, transpulmonary, through eye, through skin, through mucous membrane, per nasal, and subcutaneous, intraperitoneal, intravenous, intramuscular injection, through placental transport and suckling.
Term " in treatment effective amount " refers to when being applied to animal treat disease, the patient's condition or to reach desired result, it is sufficient to realize these of disease are treated or the amount of desired result." in treatment effective amount " will depend upon which compound, treats morbid state or desired health benefits, severity or the disease treated, desired result, age of animal and relative healths, use by way of with form, attending doctor judge animal artificial is looked after or nursing and other factors and change.The amount of " effectively " ABA will be different because of compositions and compositions, depend on particular use, concrete ABA, its salt, derivant and analog and similar factor.Therefore, it is not always able to accurate " effectively amount " is described.But, " effectively amount " suitable in any independent example can be used normal experiment to determine by this area those of ordinary skill.
Term " treatment (treating) " and " treating (treatment) " have to suffering from or the parent of the doubtful animal suffering from disease or the patient's condition or animal uses the implication being commonly understood by of rem, and refer to reverse, alleviate, suppress or slow down these term application in disease, the process of disease or the patient's condition or these diseases, disease or the patient's condition one or more symptoms, or the chance that prevention or minimizing disease, the patient's condition, disease or consequence occur, or increase the effect of specific physiological responses or health benefits.
As used herein, term " minimizing ", " containment " and " suppression " has the implication being commonly understood by alleviating or reducing.As used herein, term " carrying out " means the increase on scope or severity, advance, growth or deterioration.As used herein, the recovery of front state treated in term " recurrence " after meaning to relax a period of time.
As used herein, term " nutriment " is generally understood as any material meaning to comprise ABA, its be a part for food or liquid, food or liquid or the additive of food or liquid and its provide medical treatment or health benefits (including prevention and treatment of diseases) or its trigger independent of or exceed and do not comprise external source or raise the physiological responses of material of ABA.These products may be from following scope: the food of the nutrient of separation, dietary supplement, special diet, genetic engineering design, herbal products and processed food, for instance corn, soup, nutrition bar, beverage, tablet, capsule, solution, emulsion, rod, gel, bland, cheese, bread, fruit juice and other nutriments.
As used herein, be defined as " about " or " about " each occurrence with relevant all numerical value such as amount, percentage by weight, i.e. plus or deduct 10%.Such as, phrase " weighing scale at least 5% " should be understood " weighing scale at least 4.5% to 5.5% ".Therefore, scope of the claims contains the amount in the 10% of required value.
For the compositions used
In certain embodiments, the compositions of the present invention can be included in the vehicle being suitable for being suitable to orally ingestible.The acceptable carrier being suitable for includes solid-filling agent or diluent and aseptic aqueous solution or organic solution.Reactive compound is to be enough to provide the amount of desired effect to be present in these compositionss.
The compositions of the implementation being intended for the present invention can solid, solution, emulsion, dispersion liquid, micelle, liposome and similar form use, and the compositions wherein obtained comprises one or more active component of the mixing with the organic or inorganic carrier or excipient that are suitable to per nasal, enteral or parenteral application.
Active component can such as with generally nontoxic, physiology's upper acceptable carrier combination for tablet, pill, capsule, lozenge (troche), lozenge (lozenge), moisture or containing oil-suspending agent, dispersible powder or granule, suppository, solution, emulsion, suspension, hard capsule or soft capsule, Caplet or syrup or elixir and any other form of being adapted in use to.Possible carrier includes the glucose of solid, semisolid or liquid form, lactose, arabic gum, gelatin, mannitol, gelatinized corn starch, magnesium trisilicate, Pulvis Talci, corn starch, keratin, silica sol, potato starch, carbamide, medium chain triglyceride, glucosan and is suitable to other carriers used in preparing preparation.Additionally, used additives, stabilizer, thickening agent and stain can be made.
In another embodiment, the compositions that can prepare the present invention for intranasal, intravenous, percutaneous or is used through eye.Preparation is used for these compositionss used within the scope of art technology.
In different embodiments, the compositions of the present invention can be prepared for eating together with food.In another embodiment, the compositions of the present invention can be configured to the supplementary for food consumption, for instance as solid or liquid, such as tablet, capsule, solution, emulsion, rod, gel, bland or the like.In other embodiments, the compositions of the present invention can together with Yoghourt, oatmeal, bread, fruit juice and other food preparation.In more embodiment, the compositions of the present invention can mix with Yoghourt, oatmeal, bread, fruit juice and other food (including but not limited to provide the food of health benefits).
In different embodiments, the compositions of the present invention can be formulated as edible fluid composition.Preparation is used for the compositions of edible forms of liquid compositions within the scope of art technology.
In other embodiments, the compositions of the present invention can be applied to young baby by suckling parent, is applied to young baby by transplacental transfer from parent, uses by IV or for young baby's infant formula.
There are disease and the patient's condition that stand-by the compositions and methods of the invention treat
The present invention provides treatment and/or the method for prevention disease or the patient's condition, and it includes the compositions of the present invention of effective amount on animal administering therapeutic in need.
In another embodiment, the method for survival rate and body weight after the present invention relates to breeding and relating more specifically to increase birth, it includes the ABA of effective amount on animal administering therapeutic in need.
Another embodiment of the invention relates to the method increasing immunologic function, and it includes the ABA of effective amount on animal administering therapeutic in need.The minimizing of spleen size that this is likely to be partly due in animal and obtain.Spleen is to work to store the organ of platelet and leukocyte in filtration recirculation blood simultaneously, and platelet and leukocyte all work in immune system.
Preferred scope for the ABA of the upper effective amount for the treatment of of distinct methods is from about 0.1mg/kg/ days to about 1000mg/kg/ days.In treatment, the preferred scope of the ABA of effective amount is from about 10mg/kg/ days to about 1000mg/kg/ days.In treatment, the particularly preferred scope of the ABA of effective amount is from about 50mg/kg/ days to about 500mg/kg/ days.In treatment, the particularly preferred scope of the ABA of effective amount is from about 50mg/kg/ days to about 200mg/kg/ days.
Preferred compositions comprises S-ABA.
One embodiment of the invention is the fluid composition that can be prepared as ready-to-use diluent or dilutable concentrate.Embodiment of the present invention can be the solution containing the ABA more than weighing scale 0.5% to 50%.The risk that dilutable concentrate can directly be diluted in water to precipitate without effective ingredient to final utilization concentration or any intermediate dilute degree.Preparing cheap, process containing aquatic product and using safety and ABA active component to stablize under storage and transportation conditions according to one embodiment of the invention.The people with technology generally in the art is able to determine how to prepare final concentration of aqueous solution to be directly used in animal causing the precipitation of active component and without stirring that is consuming time and that require great effort to be brought in solution by active component without too much experiment without any chance.
The compositions of the present invention can be prepared as independent unit dose or multiple independent unit dose.As used herein, " unit dose " means the discrete amount of the compositions of the active component comprising scheduled volume.The amount of active component is generally equivalent to dosage or the one part of the active component by being applied to animal.
The compositions of the present invention can be liquid or lyophilization or goods dry otherwise and include dilution, and it has different buffering inclusions (such as Tris-HCl, hydrochlorate, phosphate), pH and ionic strength, additive (such as avoiding albumin or the gel of Surface absorption), detergent (such as polysorbas20TM, Tween 80TM, PluronicF68TM, bile salt), solubilizing agent (such as glycerol, polyglycereol), antioxidant (such as ascorbic acid, sodium sulfite), preservative (such as thimerosal TM, benzylalcohol, p-Hydroxybenzoate), dilatant or isoosmotic adjusting agent (such as lactose, mannitol), polymer such as Polyethylene Glycol is covalently bound with protein, with complexing of metal ion, or material is mixed at poly-compounds such as polylactic acid, polyglycolic acid, among the microparticle formulation of hydrogel etc. or on or mix at liposome, microemulsion, microgranule, single or multiple lift adipose capsule, on blood shadow or protoplasm.These compositionss will affect physical state, dissolubility, degree of stability, internal rate of release and internal removing speed.Control or sustained-release composition includes the goods in lipotropy storage agent (such as fatty acid, wax, oil).
And, as used herein, acceptable carrier is that those skilled in the art know, and include but not limited to 0.01-0.1M and preferably 0.05M phosphate buffer or 0.9% saline.Additionally, these acceptable carriers can be moisture or water-free solution, suspension and emulsion.The example of water-free solvent is propylene glycol, ethylene glycol, vegetable oil such as olive oil and injectable organic ester such as ethyl oleate.Aqueous carrier includes water, and containing alcohol/aqueous solution, emulsion or suspension, including saline and buffer medium.
Parenteral vehicle includes sodium chloride solution, woods grignard glucose, glucose and sodium chloride, lactic acid Green and fixed oil.Intravenous vehicles include liquid and supplementary, electrolyte replenisher such as based on woods grignard glucose those and the like.Can there are preservative and other additives, for instance antibacterial, antioxidant, finishing agent, noble gas and the like.
Control or sustained-release composition according to the present invention include the goods in lipotropy storage agent (such as fatty acid, wax, oil).The present invention includes equally with polymer (such as poloxamer or poloxamin) coated microparticle compositions and the compound with the antibody of anti-tissue-specific receptors, part or antigen coupling or the ligand coupling with tissue-specific receptors.Other embodiments of compositions according to the present invention include being coated for the particulate form of different administration approach (including parenteral, transpulmonary, per nasal and oral), protectiveness, protease inhibitor or penetration enhancers.
The half-life being greatly prolonged than the compound of corresponding unmodified in venous blood is shown after injection by the compound of the covalently bound modification of water-soluble polymer such as Polyethylene Glycol, Polyethylene Glycol and the copolymer of polypropylene glycol, carboxymethyl cellulose, glucosan, polyvinyl alcohol, polyvinylpyrrolidone or polyproline is known.These are modified can increase compound dissolubility in aqueous solution equally, eliminate the physics and chemical stability of assembling, strengthen compound and the immunogenicity and the reactivity that greatly reduce compound.As a result, desired Biological acdtivity in vivo can by obtaining than with such polymer-compound abduction of using of less frequency or relatively low-dose with the Compound Phase using unmodified.
Preparation can individually comprise ABA or can further include pharmaceutically acceptable carrier and can be solid or liquid form such as tablet, powder, capsule, pill, solution, suspension, elixir, emulsion, spray, gel, unguentum or suppository, including rectum and transurethral suppositories.Pharmaceutically acceptable carrier includes colloid, starch, sugar, fibrous material and their mixture.The preparation comprising ABA can pass through such as to be subcutaneously implanted pill and be applied to animal.Preparation is used also by the intranasal of liquid preparation, vein, tremulous pulse, or intramuscular injection.Use and again may be by using rectal suppository or urethral bougie to realize.
The preparation that the present invention can use can be prepared by known dissolving, mixing, granulation or tablet moulding process.For Orally administered, ABA and analog are mixed with the additive being usually used in this purpose such as vehicle, stabilizer or inert diluent and are converted into by common method and be suitable to the form such as tablet used, coated tablet, hard gelatin capsules or soft gel capsule, aqueous solution, alcoholic solution or oil solution.The example of inert agents thing being suitable for be conventional tablet substrate such as with binding agent such as arabic gum, corn starch, the lactose of Gel Compositions, sucrose or corn starch, and disintegrating agent such as corn starch, potato starch, alginic acid or lubricant such as stearic acid or magnesium stearate.
The oiliness vehicle being suitable for or the example of solvent are vegetable or animal oil such as Oleum Helianthi or cod-liver oil.Preparation can be dry or wet granule.For parenteral administration (subcutaneous, intravenous, intra-arterial or intramuscular injection), if needed together with being usually used in and be applicable to material such as solubilizing agent or other auxiliary agents of this purpose, ABA and analog are converted into solution, suspension or emulsion.Example is sterile liquid such as water and oil, adds or be added without surfactant and other pharmaceutically acceptable adjuvants.Illustrative oil is those such as Oleum Arachidis hypogaeae semen in oil, animal, vegetable or synthesis source, soybean oil, or mineral oil.Generally, water, saline, D/W and relevant sugar juice and glycol such as propylene glycol or Polyethylene Glycol are preferred liquid-carriers, especially for injectable solution.
Being prepared by of pharmaceutical composition containing active component is well known in the art.These compositionss can be prepared as injectable liquid solution or suspension；But, it is possible to preparation is suitable to be dissolved in or be suspended in the solid form in liquid before the injection.Equally possible by preparation emulsifying.Active therapeutic ingredient generally mixes with pharmaceutically acceptable and compatible with active component excipient.The excipient being suitable for is such as water, saline, glucose, glycerol, ethanol or the like or its combination in any.
[52] additionally, compositions can comprise the auxiliary substance such as humidizer or emulsifying agent of a small amount of enhanced activity element utility, pH buffer agent.
Animal feed
[53] compositions of the present invention preferably by the form of animal feed and includes albumen, fat, fiber, calcium and phosphorus.Preferred feedstuff will include Semen Maydis and/or Semen Tritici aestivi, Semen sojae atricolor powder, fat, animal byproduct, meat and bone meal and vitamin and mineral.
[54] ABA can initial mixing to premix.Term " premix " expection means preparation for the original mixture containing active component and such as carrier and the forage mixture becoming final feed that is in harmonious proportion afterwards.In the present invention, generally suggestion is in order to calculate with easy to use, is mixed by the conventional feed of premix with about a tonne (MT), and result is to provide the required dosage needs of ABA to animal.When preparing the final feed of a tonne (MT), the premix of the present invention preferably comprises about 1 to 2000 and the more preferably ABA of about 5 to 500 grams.The carrier used in premix is well known to those skilled in the art and is readily determined suitable concentration.
[55] ABA can add to carrier as dry powder or liquid solution or suspension.Fashionable when adding as liquid, ABA can pass through dissolving is stirred at room temperature or is suspended in liquid.These liquid can be water or applicable solvent or be the another kind of products for animal feed of liquid form.Because the liquid dissolubility of ABA characterizes, it can form suspension.Be added to after the ABA of predetermined amount routine premix and will not by its excessive infiltration.Once be prepared for premix, afterwards premix is added to final feedstuff, preferably with the premix of 1/4th pounds (Ib.) to five pounds (Ib.) ratio than one tonne of (MT) feedstuff scope, to provide the ABA needed for every day for poultry.
[56] ABA solid or solution or liquid suspension can be fed directly to premix material and mix afterwards.Mixing such as can be completed by the horizontally or vertically agitator of standard by any of mode.Incorporation time also can be depending on the concrete composition of premix and changes and can spend and guarantees that composition is thoroughly mixed the necessary time.
[57] it is impregnated in after premix in feedstuff and is fed to poultry.In embodiment more preferably, ABA forms premix with carrier mediation and premix is directly in harmonious proportion to final feed.Although not using higher amount will to cause the evidence of any toxicity problem in handled poultry, but it affecting cost consideration.Because premix is generally increased by tonne feedstuff (as generally in the factory), the one gram of ABA adding to premix accordingly produces the ABA concentration of about 1ppm in feedstuff.Therefore, 5 grams of ABA are added to one pound of premix, be added to one tonne of (MT) feedstuff after, produce effective ABA concentration of about 5ppm.
Although ABA can mix before last feedstuff with premix material mixing, but the ABA of the amount being suitable for can directly be in harmonious proportion to feedstuff or be sprayed on feedstuff.No matter directly or via premix addition, in last feedstuff, the interpolation of preferred ABA ranges for, every about 1 to 2000 gram of metric ton (MT) feedstuff, it is more preferred to 5 to 500 grams of per metric ton (MT) feedstuff.
Feedstuff is conventional to be prepared in big hopper or blender, and wherein feed ingredient adds with descending weight order according to they content in last forage mixture.Therefore, corn that is broken or that grind will be basis.Add a small amount of composition afterwards.Micro constitutent is eventually adding.These include vitamin, medicine, growth promoter, antibiotic and the ABA in present example.Therefore, ABA can be a kind of in micro constitutent and add to feedstuff in last mediation step.Feedstuff is in harmonious proportion routine time period.
The feedstuff comprising ABA such as paste, chip or pill in a standard are also fed to domestic animal and fish with standard feeding dosage and speed.
Another embodiment of the invention is to prepare the fluid composition for ready-to-use diluent or dilutable concentrate.Embodiment of the present invention can be the solution containing the ABA more than weighing scale 0.5% to 50%.Dilutable concentrate can be directly diluted in water to final utilization concentration or to the dilution factor of any centre, without the risk of active component precipitation.Preparing cheap, process containing aquatic product and using safety and ABA active component to stablize under storage and transportation conditions according to one embodiment of the invention.The people with technology generally in the art is able to determine how to prepare final concentration of aqueous solution to be directly used in animal without excessive experiment, it does not have any chance causes the precipitation of active component and without stirring that is consuming time and that require great effort to be brought in solution by active component.
Another embodiment of the invention is ABA aqueous solution, and it works as the drinking water source of animal.The aqueous solution so supplemented can by being dissolved in drinking water by dry powder ABA or by using the liquid solution of ABA or suspension-concentrates to prepare.In drinking water, ABA preferably adds and ranges for about 1 to 2000 part of every million (ppm) or about every liter of water of 1 to 2000 milligram of ABA；More preferably about 5 to 500 parts of every million (ppm) or about every liter of water of 5 to 500 milligrams of ABA.The people with technology generally in the art is able to determine how to prepare final concentration of aqueous solution to be directly used in animal without excessive experiment, it does not have any chance causes the precipitation of active component and brought in solution by active component without stirring that is consuming time and that require great effort.
In another embodiment of the invention, ABA is once preparation may be directly applied to animal feed.Such as, as being implementation together with some enzymes, ABA can be directly used for final feed.In preferred embodiments, before feedstuff is delivered to animal, the aqueous solution of ABA such as pill in its final form is sprayed on final feedstuff.
The beneficial characteristics of the present invention can be observed by the following explanation embodiments of the invention of reference.These embodiments provide for illustrative purposes but are not intended to the scope of the present invention.
Embodiment
According to EPASubchronicToxicityTestGuidelines (EPA subchronic toxicity Testing Guideline): 870.3050-RepeatedDose28-dayOralToxicityStudyinRodents (in Rodents repeated doses oral toxicity research in 28 days) (in July, 2000)；(870.3100-90-dayOralToxicityinRodents in Rodents oral toxicity research in 90 days) (in August, 1998)；870.3650-CombinedRepeatedDoseToxicityStudywiththeReprodu ction/DevelopmentalToxicityScreeningTest (uses the combination repeated doses toxicity research of breeding/development toxicity filler test) (in July, 2000)；With 870.3200-21/28-dayDermalToxicity (21/28 day dermal toxicity) (in August, 1998), and OrganizationforEconomicCo-operationandDevelopment (OECD) GuidelinesfortheTestingofChemicals (Organization of Economy and Cooperation Development is for testing the guide of chemicals), including: No. 407 test: RepeatedDose28-dayOralToxicityStudyinRodents (in Rodents repeated doses oral toxicity research in 28 days)；No. 408 test: RepeatedDose90-dayOralToxicityStudyinRodents (in Rodents repeated doses oral toxicity research in 90 days)；Standard guide that No. 416 test: Two-GenerationReproductionToxicity (two generation breeding toxicity) and No. 410 test: RepeatedDoseDermalToxicity (repeated doses dermal toxicity): 21/28-dayStudy (research in 21/28 day) provide and program S)-(+)-abscisic acid detects.
Example from the data of these researchs is shown in hereafter.
Two generation breeding toxicity researchs
Carry out this research to determine the test substances possible side effect to breeding in the research of 2 generations.This include determining test substances on male and magnetic reproductive process (include gonad function, estrus cycle, mating behavior, become pregnant, gestation, childbirth, suckling, ablactation) and the impact of g and D on young baby.In generation, per produce minimum 1 nest.
To three groups of male and magnetic offer ABA, before copulation, continue at least 70 continuous skies in the diet.Target detection material concentration for F0 and F1 generation is 10,000,15,000 and 20,000ppm.Whole research to the matched group of 30 rat/sexes simultaneously continue to provide basal diet.About 7 weeks of F0 animal is greatly when using initial for test diet.The young baby of F1 generation it is selected to after test diet is applied to wean.The male continuation acceptance test material of F0 and F1 and a whole day before continuing to euthanasia in whole copulation.The female continuation acceptance test material of whole copulation, gestation, suckling and euthanasia F0 and F1 on the same day.For two generations (F1 and F2), select the variability that 8 sons of every nest (if possible, every kind sex 4) reduce in nest.The young baby's (if it can, 30/ sex/nest) from the pairing of F0 animal is selected to continue F1 generation.Male and the female continuous sky of exposure 127-130 of F0 and the male and female continuous sky of exposure 178-186 of F1.
Observe the appearance and behavior of all animals twice daily.Before recording male in whole experiment and copulation with suitable interval and female clinical observation during childbirth and suckling, body weight and food consumption.Allow the female childbirth of all F0 and F1 and feed their filial generation until the wean when suckling 21 days.With the suitable interval record clinical observation of F1 and F2 filial generation, body weight and food consumption.The F2 son of young for unselected F1 and all survivals is performed an autopsy on sb..To weigh from the organ selected by 1 filial generation/sex/nest of F1 and the F2 filial generation of postmortem.F0 and the F1 maternal animal of every survival accepts completely detailed gross necropsy after being respectively completed the wean of F1 and F2 young baby；Selected organ is weighed.Record spermatogenesis end of the final point male for all F0 and F1, and record has the ovary primordial follicle number female for all F0 and F1 of the fertility weakened in comparison and high exposure group and suspection.Microscopy is from the different organ of all F0 and F1 parental animal.
Breeding
Table 1 shows in response to survival rate after the birth that S-ABA process young baby increases
Table 1
Result as these data, it is seen that S-ABA adds pup survival rate after birth.Such as, the 4th to 7 day, 10,000ppm dosage produced the increase on average viability from 98.6% to 99.5% in rats.
The body weight that table 2 shows to process young baby in response to S-ABA and increases increases.
Table 2
Result as these data, it is seen that S-ABA adds young baby's body weight to be increased.Such as, by the 21st day, 10,000ppm dosage produce the increase that average young baby's body weight is from 46.8 grams to 47.9 grams in male rat.Increasing to accordingly from 44.4 grams to 45.5 grams in average young baby's weight of female rats.
This result also shows that ABA is likely to replace the preventive antibiotic being usually used in animal reproduction.
Table 3 proves to process, in response to S-ABA, the young baby's mortality level reduced
Table 3
Result as these data, it is seen that S-ABA decreases young baby's mortality rate.Such as, 10,000ppm dosage produce the decline from 4.57% to 1.24%.
Table 4 shows to process the young baby of every nest survival in response to S-ABA
Table 4
Result as these data, it is seen that S-ABA adds the number of every nest survival young baby.Such as 15,000ppm dosage produces average young baby's number from every nest 11.8 only to the increase of 13.1.
Visible other support data in table 2 below and 3, display postmortem fetus number and follicle size increase with adding S-ABA.
Table 5
Fetus data in listed postmortem
Table 6
Ovary primordial follicle counts
Immune system health
As seen in table 7 and 8, in rat, the two generation breeding toxicity researchs of S-ABA show the spleen weight reduction in male and secondary filial generation.
Table 7
Table 8
The general introduction of organ weight and relative organ weights
As shown in table/data above, the splenomegaly I of minimizing is directly associated with the mortality rate of the health breeding the improvement shown in form/data above and improvement.
Claims (12)
1. the method that after increasing birth, weight increases, it includes the suckling parent to animal in need or animal in need and uses the S-ABA of effective dose.
2. method according to claim 1, wherein said effective dose is 0.1mg/kg/ days to 1000mg/kg/ days.
3. method according to claim 1, wherein said effective dose is 10mg/kg/ days to 1000mg/kg/ days.
4. method according to claim 1, wherein said effective dose is 50mg/kg/ days to 500mg/kg/ days.
5. a method for survival rate, it S-ABA including using effective dose to maternal animal after increase young baby's birth of non-treatment purpose.
6. method according to claim 5, wherein said effective dose is 0.1mg/kg/ days to 1000mg/kg/ days.
7. method according to claim 5, wherein said effective dose is 10mg/kg/ days to 1000mg/kg/ days.
8. method according to claim 5, wherein said effective dose is 50mg/kg/ days to 500mg/kg/ days.
9. the method increasing every nest young baby's number, it S-ABA including using effective dose to maternal animal.
10. method according to claim 9, wherein said effective dose is 0.1mg/kg/ days to 1000mg/kg/ days.
11. method according to claim 9, wherein said effective dose is 10mg/kg/ days to 1000mg/kg/ days.
12. method according to claim 9, wherein said effective dose is 50mg/kg/ days to 500mg/kg/ days.
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| MX358078B (en) | 2014-01-10 | 2018-08-03 | Valent Biosciences Corp | (s)-3'-methyl-abscisic acid and esters thereof. |
| WO2016007587A2 (en) | 2014-07-08 | 2016-01-14 | Valent Biosciences Corporation | 3'-substituted-abscisic acid derivatives |
| EP3169320B1 (en) | 2014-07-17 | 2020-09-02 | Nutravis S.r.l. | A new treatment for improving the use of dietary sugar for energy purposes |
| WO2022131287A1 (en) * | 2020-12-16 | 2022-06-23 | 住友化学株式会社 | Livestock feed |
| US20230413860A1 (en) * | 2020-12-16 | 2023-12-28 | Sumitomo Chemical Company, Limited | Abscisic Acid-Mixed Pig Feed |
| MX2023009381A (en) | 2021-02-17 | 2023-08-17 | Sumitomo Chemical Co | Livestock feed. |
| AR124885A1 (en) | 2021-02-17 | 2023-05-17 | Sumitomo Chemical Co | LIVESTOCK FEED |
| WO2022176903A1 (en) | 2021-02-17 | 2022-08-25 | 住友化学株式会社 | Livestock feed |
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| US20220369630A1 (en) * | 2021-05-06 | 2022-11-24 | Stoller Enterprises, Inc. | Stable S-(+)-Abscisic Acid Nonaqueous Liquid Solutions |
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